They all have some similarities. Like the others, the mega project underway at the Center for Infection and Immunity (CII) is attempting to get at the molecular roots of chronic fatigue syndrome (ME/CFS). Like the others it’ll be searching through vast amounts of data in an attempt to uncover the unique biological signature(s)

The CII hopes to develop a molecular signature of ME/CFS

Like the Open Medicine Foundation and NIH Clinical Center projects, some of the technology has been developed in-house. We’re blessed with the attention of some of the most innovative researchers in the world.

Let’s take advantage of a recent talk by Simmaron Researcch Foundation Scientific Board member Mady Hornig in Sweden and check out the CII’s big plans for ME/CFS. (A transcript of the talk is provided on the striking, new Microbe Discovery website).

We learned recently that the internationally renowned Ian Lipkin is all in for chronic fatigue syndrome (ME/CFS); that his bucket list includes just two diseases: ours and autism. Mady Hornig certainly didn’t skimp on her vision for ME/CFS at the talk either; she wants to create a Center of Excellence for ME/CFS at the CII, and hopes that the large array of studies the Center is engaged in will lay the foundation for that.

You can’t have research centers without funding, though. The NIH has been very responsive recently, and the big Clinical Center study is very exciting, but extramural funding is where it’s at and little money thus far has flowed to outside researchers. Last year Ian Lipkin and Mady Hornig in one of the weirdest grant awards ever received money for sampling but no money for analysis (?) – and then had to drop in 500 K in to complete their sampling. It’s no wonder then that Mady Hornig (six months ago) referred to a “crisis” in funding. This, of course, is a crisis that’s been present for over 20 years.

Times are changing, though, and hopefully we’ll get some good news soon about the Trans NIH Working Group’s”strategy to reinvent ME/CFS at the NIH.

Even with this dearth of federal funding the CII, with the help of the Chronic Fatigue Initiative (funding metabolomics, proteomics, immune signatures, pathogen discovery projects), the Microbe Discovery Project, the (microbiome), the Stanford program (pathogens), the Simmaron Research Foundation (spinal fluid) and others, has put together a megaproject – a diverse, multidimensional attack focused on getting at the molecular underbelly of ME/CFS.

Check out the different stabs at ME/CFS the group is taking.

Dr. Montoya said last year to prepare for some exciting results in the pathogen study.

The Pathogen Slant – in a very large study, the CII using PCR, Mass Tag PCR (developed in Lipkin’s laboratory) and high throughput will scan for 1.7 million agents in, if I’m reading it right, 800 patients and controls. In his Spring 2015 and 2016 newsletters, Dr. Montoya said to expect some exciting results. They’re looking at viruses, bacteria, and for the first time ever in ME/CFS, fungi.

The Gut Plus Slant – (n=100) -The CII expects their microbiome analysis of the bacteria and fungi in gut will tell them a lot about immune functioning. It turns out that no less than 60% of our immune cells travel through and get altered by bacterial metabolites in the gut before they make it to the blood. They’re also looking at the throat area to see what this common collection point for pathogens might tell them. The CII has finished their first analyses of their initial gut study: the results were apparently good enough for the team to expand their study and begin taking multiple samples from the same patient over time.

It’s this kind of rigorous, dogged, longitudinal approach to ME/CFS – which no one by the way as ever done before – that they hope will put them first in line for a Center of Excellence. I don’t think anyone, ever, has watched the immune and microbiome systems over the length of time (12-18 months) the CII is. It would be very hard, indeed, to discount any pattern that consistently showed up over that period of time.

Plus, they’re building quite a biobank of samples at the same time. The CII will surely be at the top of the NIH’s list of potential ME/CFS research consortiums.

The Autoimmune Slant – Autoantibodies could conceivably be behind everything that happens in ME/CFS. The CII will be looking for autoantibodies to human cells and pathogens including viruses, bacteria and fungi. This will allow them to dig up evidence of past infections that may have triggered ME/CFS. Their search will also include those adrenergic autoantibodies recently found in POTS patients that dysregulate their heart rates.

Genetic, immune and pathogen data could come together to form a model for ME/CFS

The RNA Seq / miRNA – Gene expression Slant – Gene expression tells us which genes are doing what. This study will determine what’s happening with the immune genes in ME/CFS. Right now we might guess they’ll see increased immune gene expression early in the disease and reduced gene expression.

Since studies have shown that unique patterns of gene expression or genetics predispose people to prolonged courses of illness after an infection, this study is ripe with promise. (If I’m reading this right a paper should be out in the not too distant future.)

The CII could end up identifying:

pathogens that kick off the illness

a pattern of gene expression that makes ME/CFS patients particularly vulnerable to that pathogen and

the autoimmune reaction that grew out of an inadequate immune response that failed to quickly dispatch the pathogen.

Itraq / MRM Metabolomics ( amino acids, kynurenine, serotonin) Slant – The CII is particularly interested in how metabolomics (the search for metabolites in the blood) may be able to tell them what’s happening in gut.

Some results suggest the kynurenine pathway has gotten turned on in ME/CFS

The L-tryptophan and the kynurenine pathway is a particular focus. L-tryptophan should metabolize into serotonin, a feel good chemical involved in sleep, sex drive, vigilance and mood regulation. L-tryptophan, however, can also be captured by the kynurenine pathway which metabolizes it into some nasty products (bye-bye good feelings). The kynurenine pathway has popped up in an array of neurological and neuropsychiatric diseases.

Dr. Hornig noted their metabolomic analyses suggest the kynurenine pathway is alive and well in some ME/CFS patients. In a prior talk, she reported that their early data suggests that a subset of people with ME/CFS with low serotonin have increased immune activation ( IL-1 beta, TNF alpha, IL-12p40, and L-17F) as well.

Interestingly, interferon gamma (IFN-y) (see below) – an antiviral and proinflammatory activating cytokine, and TNF-a – a powerful pro-inflammatory cytokine, both of which may have become activated early in the disease, both push tryptophan metabolism into the kynurenine pathway.

Dr. Hornig said they were “very keen” to understand tryptophan’s role in ME/CFS.

Cytokine and Immune Arrays Slant – They are or will be examining a wide array of cytokine levels over time to pluck out the most consistent contributors to ME/CFS. Many people are interested in the role the autonomic nervous system plays in ME/CFS but the Lipkin/Hornig group may be the first to examine the role the immune system plays in causing the ANS issues and/or problems with orthostatic intolerance. Allergy related cytokines (IL-4, IL-13, IL-17A, IL-10, Eotaxin) that can affect histamine production and alter blood pressure have popped up in their studies (and eotaxin has popped in other studies). Histamine, of course, can have devastating effects of blood pressure and circulation. Dr. Hornig believes some of the “systemic fatigue” in chronic fatigue syndrome could originate here.

Similar results in spinal fluid and blood tests would provide a powerful validation for immune dysregulation in ME/CFS

The Spinal Fluid Slant – The Simmaron/CII study was not only the first study ever to document similar immune changes in the blood and spinal fluid, but it also introduced two new subsets; Dr. Peterson’s typical / atypical patietnts. Dr. Lipkin was so high on expanding the spinal fluid study that he flew out to Lake Tahoe for the first time in 20 years to rally support for it.

An expanded Simmaron/CII spinal fluid study with more participants and more testing is underway. Should testing reveal similar findings in the spinal fluid and the blood again, a powerful message would be sent that ME/CFS is a immune disease.

Treatment

People with shorter duration illnesses could possibly benefit from antibodies to IL-17A or interferon gamma that could reduce their hyperactive response to these cytokines. Many commercial antibodies, in fact, are now available. If Hornig/Lipkin can validate upregulated IL-17A or interferon gamma is present those treatments could become available to people with ME/CFS.

For the longer duration patients Dr. Hornig suggested that increasing the immune response by using Ampligen or [ an IL-1 receptor antagonist could be helpful.

Networking

The immune system doesn’t just poop out in the longer duration patients – it kind of goes bananas. An immune networking comparison in short vs longer duration patients suggested a very focused and active immune network existed in short duration patients. In the longer duration patients, though, a much more complex immune network featuring many down-regulated immune pathways was present. It’s the stark a portrayal of these two subsets that I’ve seen.

These big data studies may result in some surprises popping out.

Biomarker? – Despite the fact that interferon gamma levels were not particularly high they were incredibly predictive of short duration patients. That suggested, as Jarred Younger’s and Gordon Broderick’s work has suggested, that context is the key. It’s possible that increased IFN-y in the context of ME/CFS has unexpectedly strong effects.

Remember This – A big surprise in the longer duration patients spinal fluid was the almost complete disappearance of IL-6, a cytokine needed for memory storage and retrieval. The IL-1 receptor- antagonist (IL-1ra) was very low as well. That was an intriguing finding given that (a) the network analysis suggested that IL-1ra was a key down-regulating element in ME/CFS and (b) drugs such as Anakinra could boost it back up – and presumably stop the central nervous system down-regulation.

Conclusion

The Center for Infection and Immunity, led by Dr. Lipkin and Dr. Hornig, is engaged – largely thanks to the Chronic Fatigue Initiative as well as the Simmaron Research Foundation – in the third mega study of ME/CFS under way. Among the unique elements of this project are it’s continuing spinal fluid component, it’s strong focus on the gut and the kynurenine pathway, and it’s long term longitudinal study that could prove pivotal in validating ME/CFS as a disease.

The CII’s strong blood immune and spinal fluid studies last year probably helped the NIH agree to reinvigorate ME/CFS research. Hopefully, that’s just beginning of the role the Center will play in deciphering ME/CFS. Boasting one of the most extensive research efforts on ME/CFS, it surely it’s a strong candidate to be one of the ME/CFS research consortiums we hope will get funding.

Next Up – the Center for Infection and Immunity Replies to the NIH’S Request for Information on the next steps for ME/CFS

Ampligen has been in the FDA pipeline for so many years that it almost seems like a mirage at this point. The ME/CFS community has been praying, hoping, believing that Ampligen will be its first FDA approved drug for over twenty years. For a lot of people that hope may have died, but the drug has gotten new life recently.

A Little History

If Ampligen has failed to gain approval at least it and the company have been entertaining. Ironically, given its long and rather harrowing path through the FDA, Ampligen’s first use in an ME/CFS patient was prompted by none other than the FDA. After an ME/CFS patient with culture evidence of HHV-6 infection significantly improved clinical trials began.

Ampligen has trod a difficult path at the FDA over the past twenty years.

Problems occurred early on, however, when Hemispherx Biopharma, the drug’s maker, cut the trial duration in half, and ME/CFS patients sued at one point to get access to the drug. The early Ampligen trials in chronic fatigue syndrome ultimately sparked the publication of a hilarious novel by Floyd Skloot, Patient 002.

The company came under fire early. In the early 1990’s CAA President Kim Kenney (McCleary) said “Ampligen is a good drug in the wrong hands”. Daniel Hoth, then head of the National Institutes of Health’s AIDS drug program, went further when he told the Wall Street journal that “no professional drug company with any degree of professionalism would ever develop Ampligen the way it was developed by HEM.”

Difficult Path

Hemispherx Biopharma, though, has never had an easy time of it. In what surely must be a record for frustration for a drug company, Ampligen was moved to a different section of the FDA four times; each move eliciting a new review and different findings.

The FDA panel’s rejection of Ampligen in 2013 provided more head-shaking moments when two ME/CFS experts unexpectedly voted against it, and several non- ME/CFS experts (citing the community’s urgent needs) voted to approve it.

Hemispherx felt blindsided at the hearing by safety issues it been told had been addressed years ago, and which it didn’t feel it was given adequate time to respond to. (Since then FDA officials have said safety is not a major issue). It’s no wonder the company has felt at times that the deck has been stacked against them.

With the FDA asking for large drug trials that HB lacked the funds to produce, Ampligen finally seemed to be dead, but a new push to understand ME/CFS at the NIH may be producing a sea change for the drug.

Patients Push FDA To Approve Drug

More than anyone, ME/CFS patients know of the cost of having no FDA approved drugs. Patient outcry at the FDA denial of Ampligen in 2013 – including an 11-day hunger strike by patient Robert Miller, 5,000 signatures petitioning the FDA to reconsider, and thousands of emails from patients and Congresspeople flooding the FDA – prompted the FDA to conduct a Drug Development Workshop in 2014 and publish guidance for the industry on ME/CFS drug development.

The FDA’s effort to spur drug company interest in ME/CFS appears to have failed, however, leaving Ampligen still the only drug candidate within short-term reach of drug approval for a disease that the FDA acknowledges urgently needs approved treatments.

With NIH director Francis Collin’s commitment to reinvigorate chronic fatigue syndrome (ME/CFS) research and mentioning the possibility of an NIH funded Ampligen trial, it’s time to take another look at the “first” drug for ME/CFS.

Renewal

Thomas Equels has vowed to make the company attractive to investors

The Board of Hemispherx Biopharma (HB) responded to the new climate of interest by replacing its longtime President and CEO, William Carter, with its Chief Financial Officer, Thomas Equels. Equels vowed to whip company into better financial shape in order to attract investors who could help get Ampligen FDA approval. FDA approval of Ampligen, he declared was HB’s number one priority, and he would work arm in arm with the FDA to achieve that.

Ampligen

Ampligen is an immunomodulator that targets a portion of the immune system that fights viruses. Ampligen’s producer, Hemispherx Biopharma, was surely cheered by the assignment of a major NIH study to a neuroinfectious disease specialist, Dr. Avindra Nath.

Ampligen’s use in ME/CFS is predicated on the idea that viruses and/or immune issues are playing havoc in the disease. Ampligen is a toll -like receptor three (TLR-3) inducer. The receptor it binds to are found on antigen presenting cells such as dendritic cells that have been exposed to pathogens.

The binding of the receptor activates hundreds of genes in a cell. The side effects from most TLR inducing drugs limits their effectiveness, but Ampligen is unique among these drugs in that it does not cause cells to produce large amounts of pro-inflammatory cytokines.

Efficacy

Reports of Ampligen’s ability to dramatically improve the health of some people with ME/CFS abound.

The 90,000 doses given safely through Hemispherx Biopharma’s compassionate care program to ME/CFS patients by a handful of doctors in the U.S. have produced some startling stories of improvement and recovery.

Ampligen’s success stories attest to the drugs effectiveness in some people

Anita Patton, Mary Schweitzer, Bob Miller and Kelvin Lord have all documented their Ampligen success stories. Several experienced significant improvement while on it only to relapse while off it. Anita Patton essentially went from bed bound to normal functioning on Ampligen, back to being bed bound off of it, and then again to normal functioning when back on the drug.

Kelvin Lord’s story was perhaps most representative. He’s provided the most complete (and funniest) review of an ME/CFS patient’s experience with Ampligen in a series of blogs titled “The Ampligen Chronicles”. Faced with rapidly deteriorating health, Ampligen was Kelvin Lord’s last shot at health. To his surprise and delight it worked.

It didn’t return this businessman, flight instructor, skier and parasailor to complete health, but Kelvin did progress from being barely able to walk to be able to work 6 hours and do 45 minutes of resistance exercises a day. His brain fog, orthostatic intolerance, canker sores and extreme fatigue disappeared. He was back to being a productive human being for a major part of his day – a huge jump. (Read about it here.) Going from bed bound to productive is probably a bigger jump, it should be noted, than most FDA approved drugs provide.

(Find other stories in Health Rising’s Ampligen Resource Page.)

Of course, examples of Ampligen’s lack of efficacy can be found as well, but this is to be expected given the heterogeneous nature of ME/CFS. Until the subsets in ME/CFS can be targeted with treatments unique to them, treatment efficacy even for most effective treatments, is probably going to be fairly low – perhaps around the 30-40% mark found in Ampligen.

Studies

“The drug has not received a marketing approval despite the lack of proven efficacious agents in the treatment of this disease that can be severely debilitating and is estimated to effect over one million persons in the US.” The author

W.M. Mitchell, a Vanderbilt pathologist and HB Board member, recently published an overview of Ampligen in a pharmaceutical journal. (Mitchell recently co-authored a study which reported finding a significantly more accurate blood test for prostate cancer.)

Thirteen Ampligen trails have been done over the past 20 years or so. Nine occurred in severely ill prior fatigue syndrome patients; three of these were large multisite trials and five were open label trials measuring safety and efficacy. All told over 830 different ME/CFS patients have received over 90,000 doses of Ampligen. Most of the patients in the studies had been ill for at least 6-9 years.

The results of the trials have been positive. The first 92 person trial found significant increases in Karnofsky performance scores (p<.001), quality of life, exercise tolerance and oxygen utilization during exercise. Ampligen receiving patients also used significantly less drugs to alleviate their symptoms than placebo receiving patients.

The number of patients seeking emergency room care demonstrated how severely ill the patients in the study were, and how helpful Ampligen might be if it were available. Ampligen cut the number of patients visiting the emergency room in half (from 15% to <8%). The placebo patients stayed an average of eight days at the hospital, while the Ampligen receiving patients stayed an average of less than three days.

(In how many diseases would 15% of the patients in the clinical trial spend an average of 8 days at a hospital over the duration of the trial? This was a very severely ill cohort.)

The primary endpoint of next 234 person trial was exercise intolerance. The results, which barely reached the minimum standard of significance (p< .05/ p<.048), indicated that exercise tolerance increased on average about 22%. Overall Ampligen improved VO2 max results on the exercise test by 5.5%, and Ampligen receiving patients were able to stay on the treadmill for about nine minutes longer than placebo receiving patients.

Further analyses found 3 cohorts of patients with regards to exercise tolerance; high responders, mild responders and no responders. Overall patients on the drug improved significantly more than patients given placebo (p<.001).

As in the first study, hospital visits were significantly reduced in the Ampligen receiving cohort and Karnofsky performance scores were significantly increased.

The two clinical studies suggest that 30-40% of people with severe ME/CFS can be expected to get “clinical benefit” from Ampligen.

The trials were mostly successful, but did have their problems. The company stopped the first trial early and then modified the second trial in midstream. Even though the second trial was successful a great deal of discussion at the FDA hearing involved why the trial was modified. Records could have better kept as well.

From the ME/CFS communities perspective, though, the success of both trials was paramount. Many felt the lapses should have overlooked given the urgent need for treatments in such a large and often disabling disease. Many also felt that the positive testimony by doctors who had been using the drug for years should have been given more weight.

Conclusion

While there were some problems with the trials the drug did meet several important endpoints including increasing time on a treadmill and increased oxygen utilization. It should be noted that Ampligen has tried to move the needle on probably the most difficult factor of all to budge in ME/CFS: oxygen utilization during exercise.

Any drug providing clinical benefit to 30-40% of a population which has no approved drugs should be a slam dunk. (Less effective drugs have been readily approved in other illnesses). Hopefully, with new leadership, Hemispherx’s twenty plus year journey to bring Ampligen to market will end successfully, and the ME/CFS community will finally get its first drug approved.